U.S. patent number 4,205,061 [Application Number 05/924,764] was granted by the patent office on 1980-05-27 for oral antimicrobial compositions.
This patent grant is currently assigned to Johnson & Johnson. Invention is credited to James D. Vidra.
United States Patent |
4,205,061 |
Vidra |
May 27, 1980 |
Oral antimicrobial compositions
Abstract
Novel oral antimicrobial compositions comprising a synergistic
combination of a specific halogenated salicylanilide and a specific
quaternary ammonium compound are disclosed.
Inventors: |
Vidra; James D. (Clinton,
NJ) |
Assignee: |
Johnson & Johnson (New
Brunswick, NJ)
|
Family
ID: |
25450690 |
Appl.
No.: |
05/924,764 |
Filed: |
July 14, 1978 |
Current U.S.
Class: |
424/55;
514/161 |
Current CPC
Class: |
A61Q
11/00 (20130101); A61K 8/4926 (20130101); A61K
8/42 (20130101); A61P 1/02 (20180101); A61K
2800/59 (20130101) |
Current International
Class: |
A61K
31/625 (20060101); A61K 31/60 (20060101); A61K
31/44 (20060101); A61K 007/24 (); A61K 031/44 ();
A61K 031/60 (); A61K 031/625 () |
Field of
Search: |
;424/55,230,232,263 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
McCutcheon's Detergents & Emulsifiers, 1971 Annual p.
1..
|
Primary Examiner: Robinson; Douglas W.
Attorney, Agent or Firm: Berman; Steven P.
Claims
What is claimed is:
1. An oral antimicrobial composition comprising as the active
antimicrobial ingredients a synergistic combination of
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride wherein the 3,5-dibromo-3'-trifluoromethylsalicylanilide
and cetylpyridinium chloride are present in a ratio of from about
10:1 to about 1:10.
2. The oral antimicrobial composition of claim 1 wherein the
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride are present in an amount of from about 0.05 to about 0.20%
by weight of the total composition.
3. The oral antimicrobial composition of claim 1 wherein the
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride are present in a ratio of about 1:1.
4. A method of inhibiting the formation of dental plaque on the
teeth comprising the application thereon of an oral antimicrobial
composition comprising as the active antimicrobial ingredients from
about 0.05 to about 0.20% by weight of the composition of a
synergistic combination of
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride wherein the 3,5-dibromo-3'-trifluoromethylsalicylanilide
and cetylpyridinium chloride are present in a ratio of from about
10:1 to about 1:10.
5. The method of claim 4 wherein the
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride are present in a ratio of about 1:1.
Description
BACKGROUND OF THE INVENTION
This invention relates to "oral compositions" which term is used
herein to designate products which, in the ordinary course of
usage, are retained in the oral cavity for a time sufficient to
contact substantially all of the dental surfaces but are not
intentionally ingested. Such products include, for example,
dentifrices, mouthwashes, chewing gums, prophylaxis pastes,
non-abrasive gels, topical solutions and the like. This invention
more specifically relates to oral compositions which exhibit
antimicrobial properties which help to retard the accumulation of
dental plaque and/or calculus on the teeth and gums.
Dental plaque is a complex organic film which adheres to and coats
the oral hard and soft tissues. The formation and properties of
dental plaque are extremely important in the maintenance of oral
health since plaque harbors the bacteria which produce dental
caries, gingivitis and periodontitis. In fact, dental plaque is
composed essentially of bacterial colonies growing in an
interbacterial organic matrix that provides adherence of the
colonies to the teeth and gingiva and coherence of the colonies to
one another. Thus, the elimination or inhibition of dental plaque
is related to and beneficial in reducing the incidence of dental
caries, gingival inflammation and periodontitis.
As is well known to those skilled in the art, dental caries is
caused principally by dissolution of tooth mineral by biologically
produced intra-oral acids. Such biologically produced intra-oral
acids primarily are produced by some of the bacterial colonies that
constitute dental plaque. Gingival inflammation, which is the first
stage of the more severe periodontitis, is produced by the
inflammatory products of bacterial plaque metabolism. Among these
bacterial metabolites one can mention hydrolytic enzymes,
endotoxins and antigens. Thus, the elimination of the medium which
comprises such caries and gingivitis producing bacteria is believed
to directly affect the incidence of dental caries and
periodontitis.
The formation of dental plaque is not fully understood but it is
known to result from the growth and colonization of various strains
of oral bacteria on the surface of the teeth and gingiva. Further,
there is believed to be a direct relationship between the ability
of dental plaque to induce the precipitation (crystallization) of
calcium salts on the surface of the teeth and formation of dental
calculus.
Dental calculus is a hard deposit found on the surfaces of the
teeth which results from the precipitation of calcium salts in an
organic matrix, primarily plaque. Thus, calculus can be defined as
calcified plaque. Calculus is related to dental health since its
presence is associated with pathological changes in the bone,
gingiva and other supporting periodontal structures. Thus, the
elimination and retardation of the formation of dental plaque is an
important factor in dental hygienic and health programs not only in
the reduction of dental caries and periodontal disease but also the
reduction of the formation of dental calculus.
The utilization of antibacterial or antimicrobial agents such as
antiseptics and germicides for topical application in the oral
cavity is well known in the art. By way of explanation, an
antiseptic ordinarily is considered to be an agent which stops or
inhibits the growth of microorganisms without necessarily killing
them. In contrast, a bacteriocide or germicide is any substance
which kills or destroys bacteria. Frequently, the difference
between bacteriostatic and bacteriocidal effects is a quantitive
function of the concentration of the antibacterial agents or a
qualitative function of the agent itself.
Less irritating antiseptics find wide usage for topical application
on the oral mucosa for the control of minor infections and on dried
mucosa in preparation for needle insertion. Antiseptics too
irritating for use on soft tissue find application within the tooth
structure for root canal sterilization or cavity medication.
Germicides have also been incorporated in commercial mouthwashes
which are medicated liquids used for cleaning the mouth or treating
disease states in the oral mucous membrane.
The use of such antiseptic agents has many times resulted in severe
staining problems with the teeth which would mitigate against their
use even if they were effective against plaque.
SUMMARY OF THE INVENTION
It is an object of this invention to provide improved oral
compositions.
It is another object of this invention to provide improved oral
compositions which exhibits antimicrobial properties to aid in the
prevention of plaque and gingival diseases.
It is a further object of this invention to provide improved
antimicrobial oral compositions which do not present significant
tooth staining problems.
Other objects of this invention will be set forth in, or be
apparent from, the following detailed description of the
invention.
The foregoing objects and other features and advantages of the
present invention are achieved by oral compositions comprising a
synergistic combination of antimicrobial agents which effectively
reduce the formation of plaque without adversely staining the
teeth. More specifically, the present invention relates to oral
composition comprising a synergistic combination of a specific
halogenated salicylanilide and a specific quaternary ammonium
compound.
DETAILED DESCRIPTION OF THE INVENTION
In general, this invention comprises a synergistic combination of a
specific halogenated salicylanilide and a specific quaternary
ammonium compound. The term "synergistic combination" as used
herein refers to a mixture of two discrete compounds which display
a degree of total antimicrobial activity which is greater than the
average of the sum of antimicrobial activity of the compounds taken
individually.
The specific halogenated salicylanilide which has been found useful
in the present invention is
3,5-dibromo-3'-trifluoromethylsalicylanilide which is of the
formula ##STR1## Surprisingly
3,5-dibromo-3'-trifluoromethylsalicylanilide does not exhibit the
toxicity or photosensitivity problems which have been observed with
other halogenated salicylanilides and would therefore be
satisfactory for oral hygiene uses.
The other antimicrobial compound in the synergistic combination is
a specific quaternary ammonium compound, cetylpyridinium chloride,
which is of the formual ##STR2## The ratio of the compounds in the
synergistic combinations of this invention can vary from about 10:1
to 1:10, preferably a ratio of about 1:1.
The foregoing synergistic combination of
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride is preferably applied to the oral hard and soft tissues by
means of a carrier suitable for use in the oral cavity. Suitable
carriers include dentifrices, prophylaxis pastes, mouthwashes,
nonabrasive gels, chewing gums, topical solutions, and the like.
When used in such compositions, the synergistic antimicrobial
compositions are present in about 0.05% to about 0.20% by weight of
the total compositions. In the case of topical solutions and
mouthwashes, suitable carriers include water and other liquids.
Other carriers include various compatible plastics, e.g., nylon,
polyethylene, polypropylene and the like, and other materials,
e.g., natural bristles, wood, and the like, which may be formed
into toothbrushes or interdental stimulators and thus utilized to
apply the active agents of the present invention to the oral hard
and soft tissues. Also, other carriers include waxes, plastics, or
any other binders or sizings used on dental flosses and tapes or
chewing gum which contact the oral hard and soft tissues during use
or consumption. Indeed, substantially any device or implement
capable of supplying the active agents to the oral hard and soft
tissues may serve as a suitable carrier in accordance with this
invention.
DENTIFRICE PREPARATIONS
Compositions adapted for regular home use such as dentifrice
preparations and the like typically comprise about 20-95% by weight
of a compatible cleaning and polishing agent as a carrier suitable
for use in the oral cavity. The synergistic antimicrobial
combinations of the present invention should comprise from about
0.05% to 0.2% by weight of the dentifrice preparation.
Various compatible cleaning and polishing agents suitable for use
in the dentifrice embodiments of this invention are known in the
art including insoluble sodium metaphosphate, calcium
pyrophosphate, calcium hydrogen phosphate dihydrate, anhydrous
calcium hydrogen phosphate, and substantially water impervious
crosslinked thermo-setting, highly polymerized synthetic resins,
e.g., melamine formaldehyde resins, as described in U.S. Pat. No.
3,070,510. Preferably, zirconium silicate or mixtures of zirconium
silicate with other cleaning and polishing agents, e.g., talc, as
set forth and described in U.S. Pat. No. 3,450,813 may be used as
the cleaning and polishing agent. Also, mixtures of such polishing
agents may also be employed. The dentifrice preparations may be
prepared in a conventional manner and will usually include
additional ingredients to render the overall composition
commercially acceptable to consumers.
Dentifrices require a binder substance to impart desired textural
properties. Natural gum binders such as gum tragacanth, gum karaya
and gum arabic and seaweed derivatives such as Irish moss and
alginates, and water soluble cellulose derivatives, such as
hydroxyethyl cellulose and sodium carboxymethyl cellulose, can be
used for this purpose. Desirably, those materials are employed
which are most compatible with the antimicrobial agents. Binders
which have no ionic groups, such as hydroxyethyl cellulose, are
especially preferred; however, selected ionic binders can
occasionally be used. Improvements in texture can also be attained
by including an additional material such as colloidal magnesium
aluminum silicate. Thickening agents in an amount of from 0.5 to
5.0% by weight can also be used to form a satisfactory
dentifrice.
Dentifrices conventionally contain sudsing agents. Suitable sudsing
agents include, but are not limited to, water soluble alkyl
sulfates having from 8 to 18 carbon atoms in the alkyl radical,
such as sodium lauryl sulfate; water soluble salts of sulfonated
monoglycerides of fatty acids having from 10 to 18 carbon atoms in
the alkyl radical, such as sodium coconut monoglyceride sulfonate;
salts of fatty acid amides of taurines, such as sodium-N-methyl
palmitoyl tauride; and salts of fatty acid esters of isethionic
acid. Sudsing agents can be used in compositions of this invention
in an amount of from about 0.5% to about 5.0% by weight of the
total composition.
It is also desirable to include some humectant material in a
dentifrice to keep if from hardening. Materials commonly used for
this purpose include glycerine, sorbitol, and other polyhydric
alcohols. The humectants can comprise up to 35% of the toothpaste
composition. Flavoring materials may be included in dentifrice
formulations including small amounts of oils of wintergreen and
peppermint and sweetening agents such as saccharin, dextrose,
levulose and xyletol.
A preferred antiplaque dentifrice preparation is given hereinafter
by way of example and is presented for the purpose of illustration
but not of limitation.
EXAMPLE I
______________________________________ % By Weight
______________________________________ glycerine 27.00
carboxymethyl cellulose, sodium 1.50 sodium saccharin 0.20 sodium
benzoate 0.50 dicalcium phosphate dihydrate 42.00 dicalcium
phosphate anhydrous 5.00 Arlasolve 200 (polyoxyethylene 20
isohexadecylether) 0.90 3,5-dibromo-3'-trifluoromethyl-
salicylanilide cetylpyridinium 0.05 cetylpyridinium chloride 0.05
deionized water q.s. to 100.00
______________________________________
PROPHYLACTIC PASTE COMPOSITIONS
Compositions of the present invention include, in addition to the
described dentifrice preparations, prophylactic paste compositions
adapted for relatively infrequent application, e.g., once or twice
a year, either professionally, i.e., by a dentist or dental
hygienist, or by self-application under professional supervision.
Prophylactic paste compositions generally differ from dentifrice
compositions in that the cleaning and polishing component thereof
is more abrasive (and as a result, is a better tooth cleaner).
Since a prophylactic paste composition is applied only once or
twice per year, a more abrasive cleaning and polishing agent may
safely be employed therein than in a dentifrice preparation, i.e.,
if the more abrasive cleaning and polishing agent were used in a
dentrifice preparation adapted for frequent application, the agent
might permanently damage the oral hard tissues.
The compatible substances previously described as suitable cleaning
and polishing agents for incorporation in dentifrice preparations
may also be employed as the cleaning and polishing component of
prophylactic paste compositions. However, in order that the desired
optimal level of cleaning and polishing effectiveness be obtained,
a different particle size and surface configuration for the
substance is needed. For example, a suitable zirconium silicate
preparation for use in a dentifrice preparation is disclosed and
claimed in U.S. Pat. No. 3,450,813 and suitable zirconium silicate
cleaning and polishing agents for use in a prophylactic paste
composition is described and claimed in U.S. Pat. Nos. 3,257,282
and 3,330,732.
Other suitable cleaning and polishing agents include mixtures of
zirconium silicate and tin dioxide (as set forth and described in
U.S. Pat. No. 3,378,445), lava pumice, silica powder, calcium
carbonate, and the like.
Prophylactic paste compositions in accordance with the present
invention are formulated containing from about 0.05% to 0.2% of the
synergistic combinations of antimicrobial agents of the present
invention by weight of the total compositions. The cleaning and
polishing agent serves as a carrier and is employed with a range of
about 20 to 80% by weight depending on the particular formulations
as is well known to one skilled in the art.
The prophylactic paste compositions are prepared in a conventional
manner and usually include additional ingredients that render the
overall composition commercially acceptable. For example,
prophylactic paste compositions typically embody conventional
components such as bleaching agents, binders, humectants, flavoring
agents and the like. A preferred prophylactic paste composition is
given hereinafter in Example II, but it should be understood that
this example is presented for the purpose of illustration and not
of limitation.
______________________________________ % By Weight
______________________________________ pumice 55.00 glycerine 15.00
carboxymethyl cellulose, sodium 1.50 sodium saccharin 0.20
cetylpyridinium chloride 0.025 3,5-dibromo-3'-trifluoromethyl-
salicylanilide 0.025 flavoring agents 0.90 water q.s. to 100.00
______________________________________
OTHER COMPOSITIONS
In addition to dentifrice and prophylactic pastes, the present
invention may be used in conjunction with other compositions, e.g.,
topical solutions, mouthwashes and non-abrasive dentifrice gels.
The synergistic combinations of the present invention are utilized
from about 0.05% to 0.2% by weight of the total compositions. A
preferred mouthwash composition is given hereinafter in EXAMPLE
III, but is should be understood that this example is presented for
the purpose of illustration and not of limitation.
EXAMPLE III
______________________________________ % By Weight
______________________________________ ethyl alcohol, 95%, USP
10.0000 3,5-dibromo-3'-trifluoromethyl- salicylanilide 0.0500
Pluronic F127 (polyoxyethylene glycol) 1.7500 glycerine 5.3000
saccharin, sodium 0.0500 monosodium glutamate 0.0496
cetylpyridinium chloride 0.0500 coloring agents 0.9000 flavoring
agents 0.2100 deionized water q.s. to 100%
______________________________________
A preferred non-abrasive dentifrice gel composition is given
hereinafter in EXAMPLE IV, but it should be understood that this
example is present for the purpose of illustration and not of
limitation.
______________________________________ % By Weight
______________________________________ Pluronic F-127
(polyoxyethylene glycol) 26.000 Arlasolve 200 (polyoxyethylene 20
isohexadecylether) 1.500 cetylpyridinium chloride 0.025
3,5-dibromo-3'-trifluoromethyl- salicylanilide 0.025 potassium
sorbate 0.150 flavoring agents 0.800 coloring agents 0.018 water
q.s. to 100% ______________________________________
In addition to the above carriers, the present invention may be
used in conjunction with various other carriers which contact the
oral hard and soft tissues during normal use. For example,
typically the bristles (either plastic or natural) of a toothbrush,
the surfaces of plastic or wooden interdental stimulator, and the
surfaces of rubber or plastic dental prophylaxis cup come into
close contact with the oral hard tissues, and thus provide a
suitable carrier for the active agents of the present invention,
with such agents being impregnated in or coated on such
carriers.
Similarly, dental flosses and dental tapes utilized to clean the
interproximal surfaces of the teeth typically include a waxy,
plastic or other material which serves as a carrier for the active
agents of the present invention. Typically, such wax may be a water
soluble wax, e.g., paraffin, or a water insoluble wax, e.g.,
polyethylene glycol, polyethylene oxide, polypropylene oxide,
methylcellulose and mixtures thereof. Plastics such as vinyl
acetate and adhesives such as polyvinyl alcohol are examples of
other carriers.
EXAMPLE V
The synergistic antimicrobial efficacy of the combinations of the
present invention can be established by the following test
procedure. A suitable substrate material, e.g., tooth enamel or a
glass slide, is treated with one of the solutions and placed in a
human plaque growth media for incubation. The solutions include
water alone, 3,5-dibromo-3'-trifluoromethylsalicylanilide alone,
cetylpyridinium chloride alone and a combination of
3,5-dibromo-3'-trifluoromethylsalicylanilide and cetylpyridinium
chloride. The concentration of the solutions containing a single
antimicrobial agent is equal to the concentration of the solution
of the combination of antimicrobial agents.
The plaque reduction of each solution is compared to the water
solution and a plaque reduction percentage is arrived at by the
following equation: ##EQU1## wherein P.sub.A is the average weight
of the plaque accumulated on the substrates treated with the
antimicrobial agent or the combination of antimicrobial agents and
P.sub.WS is the average weight of the plaque accumulated on the
substrates treated with the water solution.
The plaque reduction percentages for each solution containing a
single antimicrobial are averaged and then compared to the plaque
reduction percentage of the combination of antimicrobials. The
results of six runs are shown in Table I as follows:
Table I
__________________________________________________________________________
Average of Plaque Plaque Reduction Reduction Percentages of
Percentage of Solution % Increase Solutions Containing a of
Combination of of Plaque Run Single Antimicrobial Agent
Antimicrobial Agents Reduction
__________________________________________________________________________
1 63% 79% 25% 2 70 66 -5 (derease) 3 47 68 40 4 69 77 12 5 69 90 23
6 70 91 30
__________________________________________________________________________
As can be seen from the above results, the combinations of
antimicrobial agents exhibit a synergistic increase in plaque
reduction over the individual antimicrobials at the same
concentration levels. Run 2 did not exhibit this increase but can
be explained by the adverse microbial growth conditions
periodically observed in this type of in vitro assay.
EXAMPLE VI
The non-staining properties of the synergistic antimicrobial
combinations of the present invention are demonstrated by the
following modified Nordbo staining procedure.
This procedure is set forth in an article by H. Nordbo,
Discoloration of Human Teeth by a Combination of Chlorhexidine and
Aldehydes or Ketones In Vitro, Scand. J. Dent. Res. 79:356-361
(1971). This procedure involves the Maillard or Browning Reaction
whereby a salivary protein, such as mucin, reacts with the active
aldehyde group of carbohydrates, such as acetaldehyde, fructose and
the like, to produce a furfural-type or pigmented compound that
tenaciously adheres to an artificial enamel surface.
Three solutions were prepared each containing 0.4% mucin and 4%
acetaldehyde in a 0.1 M potassium phosphate buffer solution, pH 7,
and a final volume of 10 milliliters. To one solution 2%
chorhexidine (a known staining agent) is added and to a second
solution was added 0.25% of a mixture of cetylpydinium
chloride/3,5-dibromo-3'-trifluoromethylsalicylanilide in a 1:1
ratio. Hydroxyapatite discs were added into each 10 milliliter
solution and incubated at a temperature of 37.degree. C. for three
days and then removed. Said discs were visually examined and
analytical measurements taken to quantitate staining. The disc from
the solution containing the chlorhexidine exhibited excessive
staining whereas the disc from the solution containing the
cetylpyridinium
chloride/3,5-dibromo-3'-trifluoromethylsalicylanilide mixture
demonstrated significantly reduced staining and compared favorably
with the third solution which did not contain either the
chlorhexidine staining agent or the antimicrobial mixtures of the
present invention.
* * * * *